Thyroid cancer is the most common endocrine malignancy and the incidence is rising. Approximately 1,700 patients with thyroid cancer die each year in the U.S. and many others suffer from progressive, symptomatic disease. There are currently no effective, approved systemic therapies for patients with advanced, radioiodine- resistant disease. Novel targeted therapies and markers of disease activity are desperately needed for patients with advanced thyroid cancer. Many solid tumors share activation of the nuclear factor kappa B (NFkB) pathway including the endocrine-related cancers (thyroid, parathyroid, breast, prostate and endometrial). NFkB signaling regulates diverse processes in cancer including epithelial to mesenchymal transition (EMT), invasion, angiogenesis and metastases. Furthermore, current therapies for advanced cancer, including chemotherapy and radiation, activate the NFkB pathway, which can diminish therapeutic efficacy. A better understanding of NFkB signaling in advanced thyroid cancer will lead to selective diagnostic markers and inhibitors which will be therapeutically useful as single agents or in combination with other therapies. The current field is concentrating on long-term inhibition of this complex pathway as a potential 'targeted' cancer therapy, which will likely have many untoward side-effects since NFkB signaling is important in normal physiology, particularly immune function. This proposed application will shift the current translational research paradigm in two ways: (1) investigate rational combination therapy with intermittent blockade of the NFkB pathway in novel preclinical orthotopic and metastatic mouse models of advanced thyroid cancer that recapitulates tumor invasion as well as lymph node and distant metastases, and (2) employ a novel proteomic approach to identify NFkB-dependent secreted mediators ('secretome') of tumor angiogenesis and invasion, which will lead to more specific targeted therapies and disease markers. To accomplish these goals, the following approaches will be used: (1) Genetic and pharmacologic inhibition of the NFkB pathway alone and in combination with taxane-based chemotherapy in murine models of human thyroid cancer, (2) Comparative proteomic analysis of thyroid cancer cells with and without a genetically inhibited NFkB pathway to more broadly define the NFkB-dependent secretome in advanced thyroid cancer, (3) Genetic and functional manipulation of interleukin 8, identified as an important NFkB-dependent secreted protein in thyroid cancer, and other identified NFkB targets using in vitro and in vivo models, and (4) Use of a unique, large thyroid tumor tissue/plasma bank and preclinical mouse models to determine if IL8 and other NFkB-dependent targets may be useful molecular markers or therapeutic targets in advanced thyroid cancer. Successful completion of the proposed aims will provide novel tools to study thyroid cancer development, progression, metastases and resistance to conventional therapies. These studies will likely lead to new tumor markers and therapeutic targets to improve treatment and monitoring of patients with advanced thyroid cancer.